We continue our investigations on the pathogenesis of Creutzfeldt-Jakob Disease (CJD). I. Potential links between CJD and dementias of unknown etiology will be further explored in transmission studies. II. Features common to CJD and dementias of unknown etiology will be evaluated with morphometric and immunocytochemical techniques. Degeneration of selected groups of neurons at different stages of CJD will be assessed in this context. III. The mechanisms and nature of immortalized/transformed CJD tissue culture lines will be pursued. Lines derived from CJD brains, and normal cultures exposed in vitro to highly purified CJD fractions will be used. The involvement of oncogenes and growth factors in the transformation process will be delineated. Concomitantly, we will titrate infectivity in these cells. IV. Further purification of the infectious agent is in progress and will be invaluable for the identification of agent-specific molecules. We will test our retroviral hypothesis using novel nucleic acid strategies we developed for this purpose. We will also investigate minor protein species using 2-D electrophoresis and other methods with high sensitivity in order to identify CJD-specific proteins that are recovered under several experimental conditions.